PROJECT SUMMARY/ABSTRACT Our long-term objective is to promote appropriate, safe, and effective use of medications across the range of kidney function. Adverse drug events represent a significant source of morbidity and mortality worldwide, and people with chronic kidney disease (CKD) ? a condition afflicting >10% of adults globally ? are at particularly high risk. People with CKD often take 10 or more medications, some of which require dose adjustment in impaired kidney function. However, recommendations for medication use, dosing, and monitoring are based on limited evidence and are inconsistent. We propose to use data from 5 million participants in 5 international cohorts to identify and validate medication-adverse event associations in order to inform safer health care in the ambulatory setting. First, we will assess the most frequently used medications according to glomerular filtration rate (GFR) and albuminuria, as well as patterns of use associated with CKD stage. We will then focus early work on commonly-used medications for which there is insufficient evidence to guide risk-benefit assessment in CKD. Second, we will define and abstract outcomes of interest, including possible sequelae of medication use, such as acute kidney injury, gastrointestinal bleeding, and electrolyte abnormalities, and test their associations with CKD stage. Third, we will link medication use to adverse outcomes across the spectrum of kidney function, comparing medication users to non-users through sophisticated pharmacoepidemiology techniques. We will specifically evaluate for thresholds of kidney function in which risks of adverse drug event increase, as well as concomitant patient characteristics or use of medications that alter risks. Each aim will be performed individually in one of the cohorts, replicated in the others, and then meta-analyzed. The investigative team has extensive experience in big data, pharmacoepidemiology techniques, and meta-analyses, including direct experience with each of the proposed cohorts. The project will inform objective assessment of the risks associated with many medications across the spectrum of kidney function, including both GFR and albuminuria. Results will allow for the advancement of prevention efforts, including the design of evidence-based tools for individualized clinical decision-making in ambulatory medicine, leading to the safer use of medications in all patients.